RESUMO
Polyamine synthesis represents one of the most profound metabolic changes during T cell activation, but the biological implications of this are scarcely known. Here, we show that polyamine metabolism is a fundamental process governing the ability of CD4+ helper T cells (TH) to polarize into different functional fates. Deficiency in ornithine decarboxylase, a crucial enzyme for polyamine synthesis, results in a severe failure of CD4+ T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage-defining transcription factors across TH cell subsets. Polyamines control TH differentiation by providing substrates for deoxyhypusine synthase, which synthesizes the amino acid hypusine, and mice in which T cells are deficient for hypusine develop severe intestinal inflammatory disease. Polyamine-hypusine deficiency caused widespread epigenetic remodeling driven by alterations in histone acetylation and a re-wired tricarboxylic acid (TCA) cycle. Thus, polyamine metabolism is critical for maintaining the epigenome to focus TH cell subset fidelity.
Assuntos
Linhagem da Célula , Poliaminas/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromatina/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Colite/imunologia , Colite/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Epigenoma , Histonas/metabolismo , Inflamação/imunologia , Inflamação/patologia , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ornitina Descarboxilase/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Fatores de Transcrição/metabolismoRESUMO
Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.
Assuntos
Pirimidinas , Ciclo Celular , Diferenciação CelularRESUMO
How lipidome changes support CD8+ effector T (Teff) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIPn with 3-4 double bonds), Teff cells have unique PIPn marked by saturated fatty acyl chains (0-2 double bonds). PIPn are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP2) exclusively supported signaling immediately upon T cell antigen receptor activation. In late Teff cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP2 into downstream mediators, waned, and saturated PIPn became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP2 with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIPn impaired Teff cell fitness and function, even in cells with abundant polyunsaturated PIPn. Glucose was the substrate for de novo PIPn synthesis, and was rapidly utilized for saturated PIP2 generation. Thus, separate PIPn pools with distinct acyl chain compositions and metabolic dependencies drive important signaling events to initiate and then sustain effector function during CD8+ T cell differentiation.
Assuntos
Fosfatos de Fosfatidilinositol , Fosfatidilinositóis , Fosfatidilinositóis/metabolismo , Transdução de Sinais , Fosfolipases Tipo C/metabolismo , Linfócitos T CD8-Positivos/metabolismoRESUMO
CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.
Assuntos
Proteínas Quinases Ativadas por AMP , Mitocôndrias , Células Th17 , Glutamina/metabolismo , Interleucina-17/metabolismo , Mitocôndrias/metabolismo , NAD/metabolismo , Fosfoglicerato Desidrogenase/metabolismo , Serina/biossíntese , Serina/metabolismo , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Ciclo do Ácido Cítrico , GTP Fosfo-Hidrolases/deficiência , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismoRESUMO
Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψm) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψm were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψm caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor and Δψm as a mediator of mitochondrial-directed nuclear gene expression.
Assuntos
Núcleo Celular/efeitos dos fármacos , Dinoprostona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Animais , Núcleo Celular/genética , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Interleucina-4/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Macrófagos/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8+ T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8+ T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Febre/imunologia , Mitocôndrias/metabolismo , Biossíntese de Proteínas , Animais , Antineoplásicos/metabolismo , Linfócitos T CD8-Positivos/ultraestrutura , Citocinas/biossíntese , Glucose/metabolismo , Leucemia Mieloide/imunologia , Leucemia Mieloide/patologia , Leucemia Mieloide/prevenção & controle , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mitocôndrias/ultraestrutura , Modelos Biológicos , TemperaturaRESUMO
The role of microtubules (MTs) in the control and dynamics of the immune synapse (IS) remains unresolved. Here, we show that T cell activation requires the growth of MTs mediated by the plus-end specific protein end-binding 1 (EB1). A direct interaction of the T cell receptor (TCR) complex with EB1 provides the molecular basis for EB1 activity promoting TCR encounter with signalling vesicles at the IS. EB1 knockdown alters TCR dynamics at the IS and prevents propagation of the TCR activation signal to LAT, thus inhibiting activation of PLCγ1 and its localization to the IS. These results identify a role for EB1 interaction with the TCR in controlling TCR sorting and its connection with the LAT/PLCγ1 signalosome.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Fosfolipase C gama/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Sequência de Aminoácidos , Western Blotting , Imunofluorescência , Humanos , Imunoprecipitação , Células Jurkat , Ativação Linfocitária , Proteínas Associadas aos Microtúbulos/genética , Dados de Sequência Molecular , Fosforilação , Ligação Proteica , Receptores de Antígenos de Linfócitos T/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Homologia de Sequência de Aminoácidos , Linfócitos T/metabolismo , Imagem com Lapso de Tempo , Técnicas do Sistema de Duplo-Híbrido , Tirosina/metabolismoRESUMO
Extracellular vesicles (EVs), a term that includes both exosomes of endocytic origin and vesicles derived from plasma membranes, are continuously secreted by cells to the extracellular environment, and represent a novel vehicle for cell-cell communication. Exosomes contain specific repertoires of proteins and RNAs, indicating the existence of mechanisms that control the sorting of molecules into them. Although the molecular mechanisms that regulate the loading of proteins into exosomes have been studied for years, the sorting of RNA has been elusive until recently. Here we review the molecular mechanisms that control the sorting of molecules into exosomes, with special attention to the sorting of RNA. We also discuss how the cellular context affects the composition of exosomes, and thus the outcome of the communication between the exosome-producer and recipient cells, with particular focus on the communication between tumor cells and with cells of the tumor microenvironment.
Assuntos
Exossomos/metabolismo , Transporte Biológico/fisiologia , Comunicação Celular/fisiologia , Humanos , Proteínas/metabolismo , RNA/metabolismo , Microambiente Tumoral/fisiologiaRESUMO
During antigen-specific T-cell activation, mitochondria mobilize towards the vicinity of the immune synapse. We show here that the mitochondrial fission factor dynamin-related protein 1 (Drp1) docks at mitochondria, regulating their positioning and activity near the actin-rich ring of the peripheral supramolecular activation cluster (pSMAC) of the immune synapse. Mitochondrial redistribution in response to T-cell receptor engagement was abolished by Drp1 silencing, expression of the phosphomimetic mutant Drp1S637D and the Drp1-specific inhibitor mdivi-1. Moreover, Drp1 knockdown enhanced mitochondrial depolarization and T-cell receptor signal strength, but decreased myosin phosphorylation, ATP production and T-cell receptor assembly at the central supramolecular activation cluster (cSMAC). Our results indicate that Drp1-dependent mitochondrial positioning and activity controls T-cell activation by fuelling central supramolecular activation cluster assembly at the immune synapse.
Assuntos
GTP Fosfo-Hidrolases/metabolismo , Sinapses Imunológicas/fisiologia , Sinapses Imunológicas/ultraestrutura , Linfócitos/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/metabolismo , Dinaminas , GTP Fosfo-Hidrolases/antagonistas & inibidores , GTP Fosfo-Hidrolases/genética , Inativação Gênica , Humanos , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/genética , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8+ T cell pool. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
Assuntos
Autofagia , Linfócitos T CD8-Positivos , Humanos , Animais , Camundongos , Dinoprostona , Genes Mitocondriais , GlutationaRESUMO
Immune cells must adapt to different environments during the course of an immune response. We studied the adaptation of CD8 + T cells to the intestinal microenvironment and how this process shapes their residency in the gut. CD8 + T cells progressively remodel their transcriptome and surface phenotype as they acquire gut residency, and downregulate expression of mitochondrial genes. Human and mouse gut-resident CD8 + T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We found that the intestinal microenvironment is rich in prostaglandin E 2 (PGE 2 ), which drives mitochondrial depolarization in CD8 + T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE 2 sensing promotes CD8 + T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell population. Thus, a PGE 2 -autophagy-glutathione axis defines the metabolic adaptation of CD8 + T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
RESUMO
Type 2 immunity is associated with adipose tissue (AT) homeostasis and infection with parasitic helminths, but whether AT participates in immunity to these parasites is unknown. We found that the fat content of mesenteric AT (mAT) declined in mice during infection with a gut-restricted helminth. This was associated with the accumulation of metabolically activated, interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and extracellular matrix (ECM)-producing stromal cells. These cells shared transcriptional features, including the expression of Dpp4 and Pi16, with multipotent progenitor cells (MPC) that have been identified in numerous tissues and are reported to be capable of differentiating into fibroblasts and adipocytes. Concomitantly, mAT became infiltrated with resident T helper 2 (TH2) cells that responded to TSLP and IL-33 by producing stromal cell-stimulating cytokines, including transforming growth factor ß1 (TGFß1) and amphiregulin. These TH2 cells expressed genes previously associated with type 2 innate lymphoid cells (ILC2), including Nmur1, Calca, Klrg1, and Arg1, and persisted in mAT for at least 11 months after anthelmintic drug-mediated clearance of infection. We found that MPC and TH2 cells localized to ECM-rich interstitial spaces that appeared shared between mesenteric lymph node, mAT, and intestine. Stromal cell expression of epidermal growth factor receptor (EGFR), the receptor for amphiregulin, was required for immunity to infection. Our findings point to the importance of MPC and TH2 cell interactions within the interstitium in orchestrating AT remodeling and immunity to an intestinal infection.
Assuntos
Imunidade Inata , Interleucina-33 , Tecido Adiposo/metabolismo , Anfirregulina , Animais , Citocinas/metabolismo , Dipeptidil Peptidase 4 , Receptores ErbB , Linfócitos , Camundongos , Células Th2 , Fator de Crescimento Transformador beta1RESUMO
Adipose tissue (AT) plays a central role in systemic metabolic homeostasis, but its function during bacterial infection remains unclear. Following subcutaneous bacterial infection, adipocytes surrounding draining lymph nodes initiated a transcriptional response indicative of stimulation with IFN-γ and a shift away from lipid metabolism toward an immunologic function. Natural killer (NK) and invariant NK T (iNKT) cells were identified as sources of infection-induced IFN-γ in perinodal AT (PAT). IFN-γ induced Nos2 expression in adipocytes through a process dependent on nuclear-binding oligomerization domain 1 (NOD1) sensing of live intracellular bacteria. iNOS expression was coupled to metabolic rewiring, inducing increased diversion of extracellular L-arginine through the arginosuccinate shunt and urea cycle to produce nitric oxide (NO), directly mediating bacterial clearance. In vivo, control of infection in adipocytes was dependent on adipocyte-intrinsic sensing of IFN-γ and expression of iNOS. Thus, adipocytes are licensed by innate lymphocytes to acquire anti-bacterial functions during infection.
Assuntos
Sinais (Psicologia) , Células Matadoras Naturais , Adipócitos/metabolismo , Imunidade , Interferon gama/metabolismoRESUMO
Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function.
Assuntos
Proteínas de Ligação a Ácido Graxo/fisiologia , Metabolismo dos Lipídeos , Mitocôndrias/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Linhagem Celular Tumoral , DNA Mitocondrial/metabolismo , Humanos , Interferon Tipo I/metabolismo , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/patologiaRESUMO
The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging ("inflammaging"). This cytokine storm itself acts as a systemic inducer of senescence. Blocking tumor necrosis factor-α signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescues premature aging in mice with Tfam-deficient T cells. Thus, T cells can regulate organismal fitness and life span, which highlights the importance of tight immunometabolic control in both aging and the onset of age-associated diseases.
Assuntos
Senilidade Prematura/imunologia , Proteínas de Ligação a DNA/deficiência , Mitocôndrias/metabolismo , Proteínas Mitocondriais/deficiência , Multimorbidade , Linfócitos T/metabolismo , Fatores de Transcrição/deficiência , Senilidade Prematura/genética , Senilidade Prematura/prevenção & controle , Animais , Síndrome da Liberação de Citocina/imunologia , Proteínas de Ligação a DNA/genética , Feminino , Deleção de Genes , Inflamação/genética , Inflamação/imunologia , Longevidade , Masculino , Camundongos , Camundongos Mutantes , Proteínas Mitocondriais/genética , NAD/administração & dosagem , NAD/farmacologia , Aptidão Física , Linfócitos T/ultraestrutura , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity.
Assuntos
Aciltransferases/imunologia , Síndrome de Barth/imunologia , Linfócitos T CD8-Positivos/imunologia , Cardiolipinas/imunologia , Mitocôndrias/imunologia , PTEN Fosfo-Hidrolase/imunologia , Animais , Síndrome de Barth/patologia , Linfócitos T CD8-Positivos/citologia , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5AH) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.
Assuntos
Macrófagos/metabolismo , Mitocôndrias/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Poliaminas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Células Cultivadas , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteômica , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
Interaction of T cell with antigen-bearing dendritic cells (DC) results in T cell activation, but whether this interaction has physiological consequences on DC function is largely unexplored. Here we show that when antigen-bearing DCs contact T cells, DCs initiate anti-pathogenic programs. Signals of this interaction are transmitted from the T cell to the DC, through extracellular vesicles (EV) that contain genomic and mitochondrial DNA, to induce antiviral responses via the cGAS/STING cytosolic DNA-sensing pathway and expression of IRF3-dependent interferon regulated genes. Moreover, EV-treated DCs are more resistant to subsequent viral infections. In summary, our results show that T cells prime DCs through the transfer of exosomal DNA, supporting a specific role for antigen-dependent contacts in conferring protection to DCs against pathogen infection. The reciprocal communication between innate and adaptive immune cells thus allow efficacious responses to unknown threats.
Assuntos
Antígenos/imunologia , Células Dendríticas/imunologia , Vesículas Extracelulares/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Animais , Antígenos/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Expressão Gênica/imunologia , Células HEK293 , Humanos , Interferons/imunologia , Interferons/metabolismo , Células Jurkat , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/metabolismo , Linfócitos T/virologia , Vírus/imunologiaRESUMO
The function of mitochondria and lysosomes has classically been studied separately. However, evidence has now emerged of intense crosstalk between these two organelles, such that the activity or stress status of one organelle may affect the other. Direct physical contacts between mitochondria and the endolysosomal compartment have been reported as a rapid means of interorganelle communication, mediating lipid or other metabolite exchange. Moreover, mitochondrial derived vesicles can traffic obsolete mitochondrial proteins into the endolysosomal system for their degradation or secretion to the extracellular milieu as exosomes, representing an additional mitochondrial quality control mechanism that connects mitochondria and lysosomes independently of autophagosome formation. Here, we present what is currently known about the functional and physical communication between mitochondria and lysosomes or lysosome-related organelles, and their role in sustaining cellular homeostasis.